Subclinical Hypothyroidism in Pregnancy: Link to Premature Delivery

Nancy A Melville

September 27, 2016

DENVER – Pregnant women with subclinical hypothyroidism show 50% higher rates of premature delivery, but not other complications, compared with those with normal thyroid function, according to a new research presented here at the American Thyroid Association (ATA) 2016 Annual Meeting.

And in a separate small study also reported at the meeting, those with subclinical hypothyroidism treated during pregnancy showed reductions in some complications.

Lead author of the first study, Sun Y Lee, MD, of department of endocrinology at the Boston University School of Medicine, Massachusetts, told Medscape Medical News: "Our finding of increased prematurity in offspring of mothers with elevated thyroid-stimulating hormone [TSH] during pregnancy adds to the evidence potentially advocating for thyroid-function testing in pregnant women."

The issue of screening for subclinical hypothyroidism in pregnancy is the subject of debate due to conflicting data on the benefits. ATA guidelines from 2011 concluded that the evidence is insufficient to recommend for or against universal TSH screening at the first trimester and the American College of Obstetrics and Gynecology has also recommended against universal screening.

New ATA guidelines addressing the issue are expected to be published in coming months, however.

A 50% Increased Risk of Prematurity With Subclinical Hypothyroidism

The study by Dr Lee and colleagues included more than 6000 pregnant women with data on maternal TSH who were seen for prenatal care at Boston Medical Center from January 2003 to May 2014 and information on more than 5800 infants.

The authors defined subclinical hypothyroidism as trimester-specific normal TSH concentrations of 0.1 to 2.5 mIU/L for the first trimester, 0.2 to 3 mIU/L for the second, and 0.3 to 3 mIU/L for the third. Women with established thyroid disease or who had used thyroid medication or lithium were excluded from the analysis.

High trimester-specific TSH concentrations were observed in 363 (6.3%) subjects (median, 3.33; range, 2.51–22.38 mIU/L). Of these, thyroid peroxidase (TPO) antibody status was available for 281 women, of whom 5% were TPO-antibody positive.

The results showed that those with elevated serum TSH levels during any trimester of pregnancy had a significantly higher risk of a premature delivery, compared with those with normal serum TSH levels (odds ratio, 1.52; 95% CI 1.06–2.16; P = .02), with prematurity defined as birth at less than 37 weeks' gestation.

"We found that maternal serum TSH levels above the trimester-specific range in pregnancy were associated with 50% increased risk of prematurity in offspring," said Dr Lee.

Higher serum TSH concentrations were not associated with an increased risk of any other pregnancy or prenatal complications, however, including fetal loss, placental abruption, preeclampsia/eclampsia, gestational hypertension, gestational diabetes, cesarean section, neonatal death, neonatal respiratory distress syndrome, congenital malformation, neonatal admission to intensive-care unit, or low birth weight, and there were no neonatal deaths.

These findings are consistent with previous studies on outcomes of maternal subclinical hypothyroidism, including the 2013 Generation R Study, also of nearly 6000 women (J Clin Endocrinol Metab. 2013;98):4382-4390), which showed increased risk of prematurity with an odds ratio (OR) of 1.87 in women with TSH concentrations in the 97.5th percentile (4.01 mIU/L) compared with those with normal thyroid function and an OR of 2.54 for those with hypothyroxemia and free T4 levels in the lowest fifth percentile.

Other studies have also linked subclinical hypothyroidism in pregnancy to a potential increased risk in miscarriage, including a 2014 study reported by Medscape Medical News of 3147 women, with the risk of miscarriage ranging from OR 1.62 with TSH concentrations of 2.5 to 5.22 mIU/L to as high as OR 9.56 for women with TSH 5.22 to 10 mlU/L who were also TPO-antibody positive.

Dr Lee said that they did not see any increase in miscarriage rates in their study, but this could be because "we assessed women seen for prenatal care, [so] those with early miscarriage may not have had either thyroid function measured or may not have been seen in prenatal clinic." The study also excluded records without gestational age, so early miscarriages in those cases were not able to be reviewed, she added.

But with other studies showing no adverse effects of subclinical hypothyroidism in pregnancy, the guidelines have so far erred against universal testing. The new ATA guidelines expected later this year could change this, however.

Lower Rates of Preterm Delivery in Those Treated With Low-Dose Levothyroxine

In the separate study presented at the ATA meeting, researchers delved further into this issue, looking at the effects of treatment for subclinical hypothyroidism in 56 pregnant women who were TPO-antibody negative and had subclinical hypothyroidism who were seen at the Mayo Clinic, in Rochester, Minnesota, between January 2011 and December 2013.

Criteria for subclinical hypothyroidism was TSH above 2.5 mIU/L for the first trimester or above 3 mIU/L for the second and third trimester, but less than 10 mIU/L.

Baseline TSH levels were significantly higher in the group receiving treatment: median 4.9 mIU/L vs 3.5 mIU/L in those not receiving treatment (P < .001), which first author Spyridoula Maraka, MD, said likely explained why those patients were more likely to have been offered therapy.

The comparison of those who were treated with levothyroxine (LT4; n = 22) with those who were not (n = 34) showed a reduction in preterm deliveries in the treatment group (4.6% vs 23.5%), as well as lower rates of pregnancy loss, gestational hypertension, and preeclampsia; however, due to the small number of patients, the differences did not reach statistical significance.

In terms of neonatal outcomes, there were no cases of low birth weight in the treatment group, compared with 14.3% in the untreated group; however, again, the difference was not statistically significant (P = .13).

Two women in the treatment group developed gestational diabetes, compared with one in the no-treatment group, and four in the treatment group had a premature rupture of membranes compared with three in the no-treatment group; these differences were also not significant.

"While the association was not statistically significant, we found a clinical association of LT4 therapy with a lower incidence of pregnancy loss, preterm delivery, offspring with low birth weight, low Apgar scores, and neonatal intensive-care unit admission in TPO-negative pregnant women with subclinical hypothyroidism," the authors reported.

"However there was a higher incidence of gestational diabetes and premature rupture of membranes," they add.

Dr Maraka noted that low-dose thyroxine treatment was generally effective in normalizing the women's TSH levels.

"We found that about two-thirds of women in the study were able to have their TSH normalized with just 50 μg of LT4," Dr Maraka told Medscape Medical News.

Unexpectedly, some women had normalization of TSH levels even without treatment, she noted.

"Interestingly, even some women who were not treated eventually normalized, and what we think happens is in the first weeks of pregnancy, the thyroid is under the most stress and then things get better, but we're just speculating," she concluded.

Dr Lee and Maraka had no relevant financial relationships.

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American Thyroid Association (ATA) 2016 Annual Meeting; September 23, 2016; Denver, Colorado. Abstract 10, Poster 46.

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